Infection in the neonatal

period

Iwona Maroszyńska

Polish Mother’s Health Centre

Classification

• Early onset

– 24 hours - 85%
– 24 - 48 hours - 5%
– 48 hours-6 -days 10%

• Late onset

– After 6 day
– After 3 day

Classification

• Very early infection

– 12 hours

• Early infection

– 12-72 hours

• Late infection

Pathogenesis of early

infection

• Acquisition of microorganisms from the

mother

– Transplacental infection
– Ascending

•Colonisation of the mother's

genitourinary tract

•Colonisation of birth canal at

delivery

Etiology of early infection

• B Streptococcus (GBS)
• Escherichia coli
• Haemophilus influenzae
• Listeria monocytogenes

Sexually Transmitted

Diseases

• Gonorrhea
• Syphilis
• Herpes simplex virus (HSV)
• Cytomegalovirus (CMV)
• Hepatitis
• HIV
• Trichomonas vaginalis
• Candida species

TORCH Infections

• T – Toxoplasmosis
• O – Other
• R – Rubella
• C – Cytomegalovirus
• H - Herpes

Pathogenesis of the late

infection

• Colonisation of the neonates from the

environment :

– The infant's skin
– Respiratory tract
– Conjunctivae
– Gastrointestinal tract
– Umbilicus

Vectors for the colonization

• Vascular or urinary catheters
• Intubation tube
• Chest tube
• Contact from caregivers with bacterial

colonization

Etiology

• The infectious agents associated with neonatal

sepsis have changed over the past 50 years

• S aureus and E coli were the most common

infectious hazards for neonates in the 1950s in

the United States

• GBS then replaced S aureus as the most

common gram-positive agent, causing early-

onset sepsis during the next decades

• During the 1990s, GBS and E coli continued to

be associated with neonatal infection;

however, coagulase-negative S epid. and S

aureus are now observed more frequently

Etiology

• Gram positive germs

– Coagulase-negative staphylococci

• Staphylococcus epidermidis

– Staphylococcus aureus
– GBS

• Gram negitive germs

– E coli
– Klebsiella
– Pseudomonas
– Enterobacter
– Serratia, Acinetobacter

• Fungi

– Candida

Late Viral Infection

• Meningoencephalitis and neonatal

sepsis syndrome

– Adenovirus
– Enterovirus
– Coxsackievirus
– RSV

• Bacterial organisms with increased

antibiotic resistance have emerged and
have further complicated the
management of neonatal sepsis

• Infants with lower birth weight and

infants who are less mature have
increased susceptibility to these
organisms

Coagulase negative strains

• Increasingly seen as a cause of nosocomial or

late-onset sepsis, especially in the premature
infant

• It is considered the leading cause of late-

onset infections for preterm babies

• Its prevalence is related to its preference for

the plastic mediums found in cannulas and
shunts, which increases its introduction via
umbilical catheters and other indwelling lines

Coagulase negative

staphylococci

• The bacterial capsule polysaccharide

adheres well to the plastic polymers of
the catheters

• Proteins found in the organism [AtlE and

SSP-1] enhance attachment to the
surface of the catheter

• The adherence creates a capsule

between microbe and catheter, which
prevents C3 deposition and phagocytosis

Coagulase negative

staphylococci

• The toxins formed by this organism have

been associated with necrotizing
enterocolitis

• Coagulase-negative Staphylococcus is a

frequent contaminate of blood and
cerebrospinal fluid (CSF) cultures;
therefore, it can be a false indicator of
coagulase-negative staphylococcal
septicemia

Frequency - early infection

USA

• Frequency 7-

13%

• Positive blood culture 3-8%

– Gram (+) 60%
– Gram (-) 14%
– Other 26%

ICZMP

11,5%

28%

57%
29%
Fungi 14%

28%

0,9%

N of patients in
NICU.

infection

CNS infections

Frequency of late infection

• USA 5,2% - 30,4%
• Europe 8% – 10%
• ICZMP

– Sepsis - 28%

• Positive blood culture – 82%
• Sepsis complcated by CNS infection -

11%

– CNS infection – 0,9%

• with sepsis 78%

– Serious infections – 29%

Staph. epid. 31

Strept. B 3,5

Staph. aureus 7

Staph. sp. 26

Ent. faec. 5,3

E. coli 8

Klebsiella 12

Enerobacter 1,8

Pseudomonas 1,2

Acinetob. 0,6

Grzyby 2,3

Gram (+) – 73%

S. Epi
31%

Strept.-
3,5%

Gram (-) –
24%

Fungi
2,3%

Staph. sp.

Enterococcus
faec. 5,3%

Klebsiella

sp. 12%

7%

S.aure
us

8% E. coli

Mortality/Morbidity

• The mortality rate - 50%
• Infection is a major cause of fatality during

the first month of life, contributing to 13-15%
of all neonatal deaths

• Neonatal meningitis occurs in 2-4 cases per

10,000 live births

• Mortality in the NICU related to the sepsis

– USA 11%
– ICZMP 7%

Risk factors – early infection

• Maternal GBS colonization (especially if

untreated during labor)

• Premature rupture of membranes

(PROM) Prolonged rupture of
membranes

• Prematurity
• Chorioamnionitis

Predisposing factors – early

infection

• Low Apgar score (<6 at 1 or 5 min),

• Maternal fever greater than 101°F (38.4°C)

• Maternal urinary tract infection

• Poor prenatal care

• Poor maternal nutrition

• Low socioeconomic status

• Recurrent abortion

• Maternal substance abuse

• Low birth weight

• Difficult delivery

• Birth asphyxia

• Meconium staining amniotic fluid

Maternal GBS status

 Colonisation of the maternal gastrointestinal

tract and birth canal

 Approximately 30% of women have

asymptomatic GBS colonisation during
pregnancy

 Neonatal GBS infection - 2 neonates per 1000

live births

 The highest risk of perinatal transmission

 Heavy GBS colonisation
 Chronically positive cultures for GBS have

Maternal GBS status

 Heavy colonization at 23-26 weeks of

gestation is associated with prematurity
and low birth weight

 Intrapartal chemoprophylaxis of women

with positive cultures for GBS has been
shown to decrease the transmission of
the organism to the neonate during
delivery

PROM

 Response to an untreated infection of the

urinary tract or birth canal

 Association with previous preterm delivery,

uterine bleeding in pregnancy, and heavy
cigarette smoking during pregnancy

 Rupture of membranes without other

complications for more than 24 hours prior to
delivery is associated with a 1% increase in
the incidence of neonatal sepsis

 PROM accompanying the chorioamnionitis the

incidence of neonatal infection is quadrupled

Prematurity

 Preterm infants are more likely to require

invasive procedures, such as umbilical
catheterization and intubation

 Premature infants have less immunologic

ability to resist infection

 Prematurity is associated with infection from

CMV, HSV, hepatitis B, toxoplasmosis,
Mycobacterium tuberculosis, Campylobacter
fetus, and Listeria species

Chorioamnionitis

• The relationship between chorioamnionitis

and other risk variables is strong.

• Suspect chorioamnionitis in the presence

of:

– fetal tachycardia,
– uterine tenderness,
– purulent amniotic fluid,
– elevated maternal WBC count,
– unexplained maternal temperature above

100.4°F (38°C)

• IV, IA kaniula
• Mechanical ventilation
• TPN
• Treatment of hydrocephalus
• High humidityty in incubators
• Chest tube
• Vesicle catheterisation

Predisposing factors – Late

infection

Clinical presentation

• Nonspecific and associated with

characteristics of the causative
organism and the body's response to
the invasion

• These nonspecific clinical signs of early

sepsis syndrome are also associated
with other neonatal diseases, such as
RDS, metabolic disorders, intracranial
hemorrhage, and a traumatic delivery

Congenital pneumonia

• Aspiration of the microorganisms during

the delivery process

• Tachypnea, irregular respirations,

moderate retracting, apnea, cyanosis,
grunting

• Neonates with intrauterine pneumonia

may also be critically ill at birth and
require high levels of ventilatory
support

Congenital pneumonia

 The colonization of the expiratory tract

 Infection with pulmonary changes
 Infiltration
 Destruction of bronchopulmonary tissue
 Inhibition of pulmonary surfactant

function

 Respiratory failure with an RDS-like

presentation

Congenital pneumonia

x-ray

 Segmental or lobar

atelectasis

 Diffuse reticulogranular

pattern

 Pleural effusions may be

observed

Acquired pneumonia

 Infectious agents exist in the

environment

 Risc factors

 Endotracheal intubation
 mechanical ventilation,

 Etiology

 Staphylococcus
 Pseudomonas species

Cardiac signs

• Initial early phase
• Pulmonary hypertension

– hydroxyl radicals
– thromboxane B2
– polysaccharide capsule of type III

Streptococcus

• Decreased cardiac output
• Hypoxemia is postulated to occur

Septic shock

• Clinical signes

– Pallor
– Poor capillary perfusion
– Oliguria
– Hypotension
– Edema

• These signes of shock are indicative of

severe compromise and are highly
associated with mortality

Metabolic problems

• Hypoglycemia
• Metabolic acidosis

– Conversion to anaerobic metabolism

• Increased oxygen requirements
• Increased metabolic rate
• Hyperactivity, respiratory effort
• Jaundice
• Increased glucose requirement

Neurologic signs - Meningitis

 Etiology

 GBS - 36%
 E coli -31%)
 Listeria species -5-10%
 Other organisms:

 S pneumoniae, S aureus, Staphylococcus

epidermis, Haemophilus influenzae, and species of
Pseudomonas, Klebsiella, Serratia, Enterobacter,

Neurologic signs - Meningitis

 Early-onset neonatal sepsis - 24-48 hours

nonneural signs dominat.

 Neurologic signs

 stupor
 irritability.

 Overt signs of meningitis occur in 30% of

cases

 Even culture-proven meningitis may not

demonstrate white cell changes in the CSF

Neurologic signs - Meningitis

 Late-onset infection - 80-90% neurologic signs
 Impairment of consciousness (ie, stupor with

or without irritability)

 Coma
 Seizures
 Bulging anterior fontanel
 Extensor rigidity
 Focal cerebral signs
 Cranial nerve signs

Neurologic signs - Meningitis

 The CSF findings

 Elevated WBC count (predominately PMNs)

 within the reference range in 29% of GBS

meningitis and 4% of gram-negative meningitis

 Elevated protein level, decreased CSF

glucose concentration

 Present in about 50% of GBS meningitis and

15 - 20% of gram-negative infections

 Positive cultures.

Neurologic signs - Ventriculitis

 Inflammation of the ventricular surface
 Exudative material at the choroid plexus externaly to

the plexus

 Ependymitis

 Disruption of the ventricular lining
 Projections of glial tufts into the ventricular lumen
 Glial bridges may develop by these tufts causing

obstruction, particularly at the aqueduct of Sylvius

 The lateral ventricles become multiloculated

 Isolation of the organisms

Neurologic signs - Arachnoiditis

• Next phase and the hallmark of meningitis

The arachnoid is infiltrated with
inflammatory cells producing an exudate

• Arachnoid fibrosis is responsible for

obstruction and hydrocephalus

• Early-onset GBS meningitis is

characterized by much less arachnoiditis
than late-onset GBS meningitis

Neurologic signs - Vasculitis

• Next phase of the arachnoiditis and

ventriculitis

• Appears within the first days of meningitis,

and become more prominent during the
second and third weeks

• Occlusion of the venous (phlebitis,

thrombosis) and arteries

– Hemorrhagic infarction

Hematologic signs

 Thrombocytopenia - 10-60% of

cases

 < 100 000/mm3
 < 50 000/mm3 - more diagnostic

 Duration - 1-3 weeks

Hematologic signs - WBC

• Normal WBC counts may be observed in as

many as 50% of cases of culture-proven
sepsis

• Not infected infants may demonstrate

abnormal WBC counts related to the stress of
delivery.

• Total neutrophil count (PMNs and immature

forms) is slightly more sensitive in
determining sepsis than total leukocyte count

Hematologic signs - Neutrofils

• Abnormal neutrophil - observed in two

thirds of infants

• Does not provide adequate confirmation

of sepsis

• Neutropenia is observed with maternal

hypertension

– severe perinatal asphyxia
– periventricular or intraventricular

hemorrhage

Hematologic signs - Neutrofils

• Neutrophil ratios - the immature-to-total

(I/T) ratio

– Immature neutrophil forms/ all neutrophils
– Tthe most sensitive indicator of sepsis

• Maximum acceptable ratio for excluding

sepsis during the first 24 hours is 0.16

• In most newborns, the ratio falls to 0.12

within 60 hours of life.

• The sensitivity - 60-90%

Gastrointestinal signs

• Colonization of the gut by organisms in

utero or at delivery by swallowing infected
amniotic fluid

• The immunologic defenses of the gut are

not mature, especially in the preterm
infant

• Bacterial overgrowth in the neonatal lumen

is a component of the multifactorial
pathophysiology of NEC

Diagnostic tests - cultures

 Blood, CSF, and urine cultures

 Aerobic cultures are appropriate for most of the

bacterial etiologies associated with neonatal
sepsis



Anaerobic cultures are indicated in neonates

with

 Abscess formation,
 Processes with bowel involvement,
 Massive hemolysis,
 Refractory pneumonia

Diagnostic tests - cultures

 A Gram stain provides early

identification of the gram-negative or
gram-positive status of the organism
for preliminary identification

 Bacterial cultures should generally

reveal the organism of infection within
36-48 hours

 The initial identification occurs within

12-24 hours of the growth

Diagnostic tests - cultures

 Urine cultures are most appropriate

when investigating late-onset sepsis

 Blood and CSF cultures are appropriate

for early and late-onset sepsis

 Because of the low incidence of

meningitis in the newborn infant with
negative cultures, clinicians may elect
to culture the CSF of only those infants
with documented or presumed sepsis

Diagnostic tests - CBC

 May be ordered serially to determine changes

associated with the infection, such as

 Thrombocytopenia
 WBC

 neutropenia
 left shift of leukocytes
 I/T ratio

Diagnostic tests - C-reactive

protein

• CRP - an acute phase protein associated with

tissue injury

• Rises within 24 hours of infection, peaks within

2-3 days, and remains elevated until the
inflammation is resolved

• Not recommended as a sole indicator of

neonatal sepsis,

• Part of a sepsis workup
• Serial study during infection to determine

response to antibiotics, duration of therapy

Imaging studies

 Chest radiographs - segmental or lobar

atelectasis, diffuse, fine, reticulogranular pattern,
and pleural effusions may also be observed.

 A CT scan - neonatal meningitis

 Blocks to CSF flow,
 Infarctions
 Abscesses
 Ventricular dilation
 Multicystic encephalomalacia
 Atrophy

Imaging studies

• Head ultrasonograms in neonates with

meningitis

– Ventriculitis,
– Abnormal parenchymal echogenicities
– Extracellular fluid

• Serially, head ultrasonograms can

demonstrate the progression of
complications

Procedures

• Lumbar puncture is warranted for early-

and late-onset sepsis

• Difficulties with obtaining sufficient or

clear fluid for all the studies

• Infants shold be positioned on their side

or sitting with support, adequate
restraint is needed to avoid a traumatic
tap.

• Because the cord is lower in the spinal

column in infants, the insertion site
should be between L3 and L4

Procedures

• If positive cultures are demonstrated, a

follow-up lumbar puncture is often
performed within 24-36 hours after
antibiotic therapy to document CSF sterility

• If organisms are still present, modification

of drug type or dosage may be required

• An additional lumbar puncture within 24-

36 hours is necessary if organisms are still
present

Treatment

• Begin antibiotics as soon as diagnostic tests are

performed

• Additional therapies have been investigated for

the treatment of neonatal sepsis; however, no
unequivocal proof that these treatments are
beneficial exists.

• These additional therapies include:

– granulocyte transfusion

– intravenous immune globulin (IVIG)

replacement

– exchange transfusion,
– use of recombinant cytokines

Treatment - early onset

infection

• Antibiotic: aminoglycoside and penicillin
• This provides coverage for:

– Gram-positive organisms, especially GBS
– Gram-negative bacteria, such as E coli.

• The specific antibiotics to be used are

chosen on the basis of maternal history
and prevalent trends of organism
colonization in individual nurseries

Treatment - late onset

infections

• Direct coverage at organisms implicated

in hospital-acquired infections,

– S aureus
– S epidermis
– Pseudomonas sp.
– Klebsiella sp.

Treatment - late onset

infection

• Most strains of S aureus produce beta-

lactamase, which makes them resistant
to penicillin G, ampicillin, carbenicillin,
and ticarcillin

• Vancomycin has been favored for this

coverage

• Overuse of this drug may lead to

vancomycin-resistant organisms

Treatment - late onset

infections

• Cephalosporins - attractive in the

treatment of nosocomial

infection

• Lack of dose-related toxicity
• Adequate serum and CSF concentration
• Resistance by gram-negative organisms

has occurred with their use

Treatment

• Sids effect of Aminoglycosides and Vancomycin

– Ototoxicity
– Nephrotoxisity

• Have caution when using them

• Check the serum level after 48 hours of treatment

to determine if levels are above those required
for a therapeutic effect

• The dosage amount or interval may need to be

changed to ensure adequate but nontoxic
coverage

Treatment

• A serum level may be warranted when

the infant's clinical condition has not
improved to ensure that a therapeutic
level has been reached

• In addition, perform renal function and

hearing screening to determine any
short- or long-range toxic effects of
these drugs

Treatment

• Negative Cultures + Significant risk for sepsis

and/or clinical signs,

– The clinician must decide whether to

provide continued treatment

– Three days of negative cultures should

provide confidence in the data

• A small number of infants with proven sepsis

at postmortem had negative cultures during
their initial sepsis workup

Treatment

•

Mother received antibiotic

therapy before delivery,

especially close to delivery

•

This may result in negative cultures in the infant who
is still ill

•

Review all diagnostic data, including cultures,
maternal and intrapartal risk factors, CSF results, the
CBC and differential radiographs, and the clinical
picture to determine the need for continued therapy

•

Treatment for 7-10 days may be appropriate, even if
the infant has negative cultures at 48 hours.

Treatment

• Bacterial meningitis

– Different antibiotic choice
– Different dosage
– Different treatment time

•14 - 21 days

Treatment - Meningitis

• Perform a follow-up lumbar puncture within 24-36

hours after antibiotic therapy has been initiated
to determine if the CSF is sterile

• If organisms are still present, modification of drug

type or dosage is required to adequately treat the
meningitis

• Continue antibiotic treatment for 2 weeks after

sterilization of the CSF or for a:

– minimum of 2 weeks for gram-positive

meningitis

– 3 weeks for gram-negative meningitis

Treatment - Meningitis

• Chloramphenicol or trimethoprim-

sulfamethoxazole has been shown to be
effective in the treatment of highly
resistant bacterial meningitis

Treatment

 Indications:

 Depletion of the storage neutrophil pool

 Difficulties
 Granulocyte transfusion - remains an

experimental treatment

 Documentation of storage pool depletion requires a

bone marrow aspiration,

 Must be administered quickly to be beneficial

 Potential adverse effects

 Graft versus host reaction
 Transmission of CMV or hepatitis B
 Pulmonary leukocyte sequestration

Treatment - IVIG

 Has been considered to provide type-

specific antibodies to improve

 opsonization and phagocytosis of bacterial

organisms

 complement activation
 chemotaxis of neonatal neutrophils

 The effect has been transient,
 Adverse effects associated with the

infusion of any blood product can occur

Treatment

Recombinant human cytokine

 Stimulation of granulocyte progenitor cells
 Benefit in animal models, especially for GBS

sepsis,

 Require pretreatment or immediate treatment

to demonstrate efficacy

 Granulocyte-macrophage colony-stimulating

factor (GM-CSF) and granulocyte colony-
stimulating factor (G-CSF) has been studied in
clinical trials, but their use in clinical
neonatology remains experimental

Suspected

early infection

CBC, CRP,Cultures

blood, gastric aspirate

Penicylin + aminoglikosid

Repeat CRP after 24-48 H.

LP

Continue antibiotics

Modification of antibioticotherapy

CRP (-)

CRP
(+)

CRP
(+)

LP

Contune antibiotics

CRP (-)

DC

antibiotics

Culture
(+)

Suspected late infection

CBC, CRP, Cultures

Blood, Urine

Penicilin + betalactamase inhibitor

aminogliside

Repeat CRP after

24-28 godz.

LB

Antibitics

Modify anitibiotics

CRP (-)

CRP (+)

CRP (+)

Continue antibiotics

CRP (-)

DC

antibiotics

Posiew (+)

Imipenem +

aminoglikozyd

Septic shock

Severe gastrointestinal symtoms

Indications for Carbapenems

• Rapid progression of infection symptoms

• Sever gastrointenstinal problems

• Septic shock

• Symptoms of DIC

• Result of blood culture – strain ESBL

Wankomycin - indication

• Blood culture – strain MRS

– Lack of improvement
– Increase of CRP

Rational antibiotic therapy

• Restrictive

– Length of therapy

• Decision within the 48-72 H
• Therapy 4-10dni

– Avoid large spectrum antibiotics

– According to the blood culture result

– Do not use prophylactic antibiotic

therapy

Supportive care

 Monitoring of blood pressure, vital signs
 Minimal touching
 Thermal comfort
 Cardiopulmonary support
 Katecholamine
 Mechanical ventilation
 Intravenous nutrition

Immunity of the neonate

Neutrophils

• Immature chemotaxis and killing capacity
• Decreased adherence to the endothelial

lining of blood vessels

• Reduced ability to marginate and leave

the intravascular area to migrate into the
tissues

• Decreased deformability
• Depresed migration

Neutrophils

• Impaired phagocytosis and killing of

bacteria especialy in clinically ill infant

• Lastly, neutrophil reserves are depleted

easily because of the diminished
response of the bone marrow, especially
in the premature infant

Macrophages

• Neonatal monocyte concentration and function

are at adult levels

• Macrophage chemotaxis is impaired and

continues to exhibit decreased function into early
childhood

• Macrophages are decreased in the lungs, in the

liver and spleen.

• The chemotactic and bacteriocidal activity and

the antigen presentation are not fully competent

• Cytokine production is decreased, which may be

associated with a corresponding decrease in T-cell
production

Limphocytes T

• Decreased number of T cells with the memory

cell surface phenotype

• The antigenically naive cells do not proliferate

as readily as adult T cells when activated

• Decreased production of cytokines

– B-cell stimulation and differentiation
– Bone marrow stimulation to granulocyte/monocyte

proliferation

• A delay of the formation of antigen specific

memory function following primary infection

Limphocytes B

• Decreased production of immunoglobulin
• Transfer of immunoglobulins (IgG) from

the mother 16 week of gestation

• The infant born prematurely has less IgG

due to the shorter period of placental
transmission of immunoglobulin

• Immunosuppressed mother

– less IgG can be transmitted to the infant

Limphocytes B

• Low level of IgM at birth

– Intrauterin infection - stimulation of IgM production

• IgG and immunoglobulin E (IgE) may be

synthesized in utero; however, only traces are
found in cord blood

• Immunoglobulin A (IgA)

– Transfer by breastfeeding
– Lack of secretion of IgA until 2-5 weeks after birth.

• Diminished response to bacterial polysaccharide

(2 years)

Natural killers

• Natural killer (NK) cells are found in

greater concentration in the peripheral
blood of neonates than in that of adults

• Diminished expression of the

membrane’s receptors

– Reducing cytolytic activity

Complenet system

• Synthesis of complement protein - 6 week of

gestational age

• Wide variability among individual neonates in the

concentration of the components of the
complement system

• Classic pathway - comparable to adult
• Decreased activity of the alternative pathway
• Decreased the terminal activity for complement
• Maturation of complement activity until 6-10

months

Opsonic properties

• Lower concentration of the proteins of

alternative pathway of complement
system

• Lower concentration of Fibronectin,
• Reduced opsonic efficiency against GBS,

E coli, and S pneumoniae

The natural barriers

• Skin and mucus membranes are broken

down easily in the premature infant

• Neonates who are ill and/or premature are

additionally at risk because of the invasive
procedures that breach their physical
barriers to infection

• Immaturity of the respiratory and

gastrointestinal system